Thyrotropin releasing hormone (TRH), a hypothalamic peptide, stimulates the anterior pituitary to synthesize and secrete thyroid stimulating hormone (TSH). TSH stimulates the release of triiodothyronine (T3) and (thyroxine) T4 from thyroglobulin and their secretion by the thyroid. T4 and T3 are secreted in a ratio of 10:1. Most circulating T3 and T4 are protein bound. Only the free fraction is metabolically active. In peripheral tissue, T4 is converted to T3, which is the active hormone that migrates into the target cell nuclei and binds to DNA.

Primary hypothyroidism is the most common thyroid disorder. In this condition, the thyroid fails to respond to TSH. The pituitary secretes more TSH in response to decreasing circulating T4 concentrations. The failing thyroid gland partially compensates by increasing the ratio of secreted T3 to T4. If this last attempt to restore homeostasis fails, the patient’s metabolic rate falls. At this stage of hypothyroidism, TSH is elevated and T4 and free T4 are decreased.

The opposite condition, hyperthyroidism or thyrotoxicosis, is caused by too much circulating T4. Graves’s disease, an autoimmune disorder caused by antibody to TSH receptors, leads to uncontrolled release of T4 and T3, which suppress circulating TSH. Serum T4, FT4, T3, and FT3 concentrations are elevated two to three times above the upper limit of normal and TSH is undetectable.

Thyroid function tests are among the most common laboratory tests. They account for 4% of all outpatient laboratory tests and 8% of laboratory charges. Traditionally, at least two thyroid function tests, thyroxine (T4) and T3 uptake (T3U), were ordered on each patient. The product of these tests was reported as the free thyroxine index (FTI) or T7. New methods for direct measurement of free T4 has eliminated the need to estimate free hormone levels with T3U and FTI.

The introduction of sensitive TSH (thyroid stimulating hormone) assays has transformed thyroid function testing from a thyroxine to a TSH based strategy. The American Thyroid Association recommends the combined use of TSH and free T4 as the most efficient combination of blood tests for diagnosis and follow-up of both ambulatory and hospitalized patients.

Testing begins with TSH, because it is the most sensitive indicator of thyroid metabolism in patients with normal pituitary gland function. TSH usually shifts out of the normal range sooner than thyroxine or FT4. Linear changes in FT4 concentration result in logarithmic changes in TSH secretion. About 85% of patients have normal TSH values and do not require further testing.

Decreased TSH values suggest primary hyperthyroidism, exogenous hyperthyroxinemia, or the effect of glucocorticoids. Subsequent measurement of FT4 serves as an index of the severity of hyperthyroidism, because TSH levels can be suppressed even by small increases in FT4. If FT4 is normal, total or free T3 should be measured to detect T3 toxicosis.

TSH Low

TSH Normal

TSH High

fT4 High

Hyperthyroid

Nonthyroid illness

Acute psychiatric illness

TSH secreting tumor

Amiodorone

Estrogen

Thyroxine resistance

TBG abnormality

TSH secreting tumor

Thyroxine resistance

fT4 Normal

Subclinical- hyperthyroid

T3 toxicosis

T4 over-replacement

Early pregnancy

Dopamine,

Levodopa

Glucocorticoids

Euthyroid

Subclinical -hypothyroid

Anti-TPO

Iodine drugs

Contrast media

Antithyroid drugs

Insufficient T4 Rx

fT4 Low

Hypopituitarism

Nonthyroid illness

Dopamine

Hypopituitarism

TBG abnormality

Nonthyroid illness

Phenytoin

Carbamazepine

Salicylate

Androgens

Hypothyroid

Insufficient T4 Rx

Anti-thyroid drugs

Iodine

Lithium

Increased TSH levels suggest primary hypothyroidism. However, the rare conditions of a TSH secreting pituitary adenoma or thyroid hormone resistance may be present. If FT4 levels are low, the patient is hypothyroid. Normal FT4 levels are consistent with either a euthyroid state or subclinical hypothyroidism. These two possibilities may be distinguished by testing for thyroid peroxidase antibodies.

Patients with pituitary disease or neuropsychiatric disorders may require more extensive testing. Pituitary tumors may produce TSH, which can cause secondary hyperthyroidism. Patients with previous thyroid ablation may have decreased TSH related to secondary hypothyroidism.

Nonthyroid illness and poor nutrition can cause many aberrations in pituitary and thyroid function. Seventeen percent of hospitalized adults have abnormal elevations or depression of TSH. In general, the more severe the illness, the more abnormal the tests. In critically ill patients, especially those receiving dopamine, TSH production is often reduced. As the illness progresses, T4 production is also reduced. A smaller group of patients with nonthyroid illness have increased serum T4 levels.

The median TSH level increases with age, starting at about age 50, in a disease free population.

Age

Median TSH (uIU/mL)

>50

1.60

>60

1.79

>70

1.98

>80

2.08

The median TSH level in the total population is 1.49 uIU/mL, which is considerably below the 5.5 uIU/mL upper limit of normal reported by most laboratories. A growing number of endocrinologists believe that a TSH result above 3.0 uIU/mL is abnormal, regardless of the fT4 result.

Reference range for TSH is 0.35 - 5.5 uIU/mL.

Reference range for free T4 is 0.8 - 1.6 ng/dL.

During the past 20 years, the upper reference limit for TSH has steadily declined from ~10 to 5.5 mIU/mL because of improvements in TSH assays and the enhanced sensitivity of thyroid antibody tests used to pre-screen subjects for reference range determinations. More than 95% of rigorously screened euthyroid volunteers have TSH values between 0.4 and 2.5. Individuals with a TSH >2.0 have an increased odds ratio of developing hypothyroidism. In the future, it is likely that the upper limit of the normal range will be reduced to 2.5.

Serum TSH levels exhibit considerable diurnal variation, with a maximum level occurring around midnight. TSH levels decrease as much as 50% by 08:00 to 09:30 a.m. The concentration then remains relatively constant until evening, with a smaller nadir in the late afternoon. Because of this significant diurnal variation, sequential specimens should be drawn at the same time of day.